Lung epithelial-specific TRIP-1 overexpression maintains epithelial integrity during hyperoxia exposure.

The onset and degree of injury occurring in animals that develop hyperoxic acute lung injury (HALI) is dependent on age at exposure, suggesting that developmentally regulated pathways/factors must underlie initiation of the epithelial injury and subsequent repair. Type II TGFβ receptor interacting protein-1 (TRIP-1) is a negative regulator of TGFβ signaling, which we have previously shown is a developmentally regulated protein with modulatory effects on epithelial-fibroblastic signaling. The aim of this study was to assess if type II alveolar epithelial cells overexpressing TRIP-1 are protected against hyperoxia-induced epithelial injury, and in turn HALI. Rat lung epithelial cells (RLE) overexpressing TRIP-1 or LacZ were exposed to 85% oxygen for 4 days. A surfactant protein C (SPC)-driven TRIP-1 overexpression mouse (TRIP-1^AECTg+ ) was generated and exposed to hyperoxia (>95% for 4 days) at 4 weeks of age to assess the effects TRIP-1 overexpression has on HALI. RLE overexpressing TRIP-1 resisted hyperoxia-induced apoptosis. Mice overexpressing TRIP-1 in their lung type II alveolar epithelial cells (TRIP-1^AECTg+ ) showed normal lung development, increased phospho-AKT level and E-cadherin, along with resistance to HALI, as evidence by less TGFβ activation, apoptosis, alveolar macrophage influx, KC expression. Taken together, these findings point to existence of a TRIP-1 mediated molecular pathway affording protection against epithelial/acute lung injury.

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